THE ROLE OF NOVEL TUMOUR SUPPRESSORS DURING DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. We have identified a number of genes that act to negatively regulate the cell cycle, 2 of which have characteristics typical of tumour suppressors. We have identified candidate genes for 3 of these mutations, all of which encode novel proteins related to mammalian proteins involved in negative regulation of cell proliferation or tumour suppressors. In this proposal we seek to determine the way in which these proteins function to control cell proliferation in Drosophila. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is likely to be highly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
THE ROLE OF A NOVEL NEGATIVE CELL CYCLE REGULATORY PATHWAY DURING ANIMAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. This proposal focuses on one of these regulators, Phyl, and the proteins that function with it, Sina and Ebi, which act to target and lead to the degradation of key proteins that negatively regulate differentiation and that promote cell proliferation. In this proposal we seek to understand how the Ebi-Phyl-SIna protein complex functions to control cell proliferation in Drosophila. In addition, we will examine whether the Sina complex also acts to inhibit cell proliferation in the mouse. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
Analysis Of The Scrib, Dlg And Lgl Tumour Suppressors In Cell Cycle Regulation Using The Drosophila Animal Model System
Funder
National Health and Medical Research Council
Funding Amount
$476,500.00
Summary
Cancer is a disease that is likely to affect 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in th ....Cancer is a disease that is likely to affect 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer-causing mutations result in up-regulation of this critical cell cycle regulator. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal focuses on a group of these regulators, the Drosophila tumour suppressors, Scrib, Dlg and Lgl, which act in a common genetic pathway to link cell polarity (cell shape) to cell proliferation. In mutants of these genes, cyclin E is up-regulated and inappropriate cell proliferation occurs. The aims of this proposal are to determine the signalling pathway and the transcription factors that act to upregulate cyclin E in scrib-dlg-lgl mutants. We will use the powerful genetics of Drosophila to examine candidate genes and to screen for novel genes involved in the upregulation of cyclin E in scrib-dlg-lgl mutants. The expected outcome of this project is to elucidate how Scrib-Dlg-Lgl act to control cell proliferation. scrib, dlg and lgl are present in mammals, therefore, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
Australian Drosophila Biomedical Research Support Facility
Funder
National Health and Medical Research Council
Funding Amount
$1,008,895.00
Summary
Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical research with a particular focus on understanding processes that result in human cancer or are associated with birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer Foundation, the National Health and Medical Research Council (NH an ....Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical research with a particular focus on understanding processes that result in human cancer or are associated with birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer Foundation, the National Health and Medical Research Council (NH and MRC) and the National Institutes of Health of the USA. This proposal seeks to establish infrastructure support for Drosophila research in the form of a central collection of key research stocks, a centralized facility for the importation of genetically defined stocks and a facility for the generation of transgenic Drosophila for use in biomedical research.Read moreRead less
The Polycomb Ezh2 Methyltransferase Regulates Satellite Cell Self-renewal
Funder
National Health and Medical Research Council
Funding Amount
$333,769.00
Summary
Skeletal muscle regeneration following injury is a tightly regulated process and any disturbance to this process, such as that which occurs with the muscular dystrophies, can greatly impair a muscle's ability to regenerate. The aim of this project is to better understand the mechanisms that control muscle regeneration, and open up new avenues for potential treatment strategies in conditions where muscle wasting and weakness are indicated.
Deciphering The Function Of Caspase-2 In DNA Damage Response And Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$808,007.00
Summary
Aberrant cell death and DNA damage response (DDR) are hallmarks of tumourigenesis. Recently we have discovered that an enzyme, caspase-2, previously implicated in cell death execution, also works in DDR and acts as a tumour suppressor. We now wish to validate these finding in preclinical models of cancer and understand precisely how caspase-2 safeguards against cancer development. These studies will help better understand tumourigenesis and may lead to the discovery of new drug targets.
Understanding The Molecular Mechanisms Of Cell Death In Radiotherapy
Funder
National Health and Medical Research Council
Funding Amount
$643,856.00
Summary
Radiotherapy (RT) is responsible for 40% of cancer cures. New technology enables RT delivery in fewer treatments using higher radiation dosages through a technique called 'ART'. While ART is effective in the clinic, the underlying mechanisms of cancer cell death are unclear. Here we show that ART induces two distinct waves of cancer cell death. We will characterize these waves of cell death and determine how to enhance tumour cell killing with pharmacological intervention.
Characterisation Of Erythropoietic Mutants Identified In A Forward Genetic Screen In Mice.
Funder
National Health and Medical Research Council
Funding Amount
$501,902.00
Summary
The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This proposal uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. Mice exposed to a chemical that induces random mutations in their genome are bred and pups with abnormal red blood cell ....The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This proposal uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. Mice exposed to a chemical that induces random mutations in their genome are bred and pups with abnormal red blood cells are identified. The responsible genetic mutation is identified and the gene is then studied to determine how it influences red blood cell production. The results of these studies provide insights into a variety of human conditions including anemia, thalassemia and sickle cell disease.Read moreRead less